The parathyroid hormone (PTH) receptors, PTH1R and PTH2R, and their ligands play diverse and important roles in the pathophysiology and pharmacology of the vascular system. PTH, PTH-related protein (PTHrP), and TIP39 affect vascular tone. Vascular calcification frequently accompanies both hypo- and hyper- parathyroidism and is a major cause of mortality in chronic renal failure. PTHrP up-regulation is associated with intima proliferation after arterial injury. Nonetheless, intervention on the PTH 1R has therapeutic potential for the treatment of calcific vasculopathy and restenosis. The signaling activities of the PTH receptors are remarkably cell-specific, and indeed, the cellular responses of "classical" PTH targets (osteoblasts and kidney cells) are fundamentally different from those of vascular smooth muscle cells (VSMC). Moreover, VSMC express both PTH1R and PTH2R and are exposed to PTH, PTHrP and TIP39. Little is known of the specific molecular events underlying PTH1R and PTH2R actions in VSMC. We hypothesize that the differences of signaling, regulation and trafficking between distinct cell types, specifically bone and vascular cells, are related to the expression and function of particular cytoplasmic adaptor proteins. Recent evidence shows that ezrin-binding protein 50 KDa (EBP50) contributes to signaling specificity and trafficking of the PTH1R. Arrestins are central determinant for receptor desensitization and contribute to the mitogenic activities of the PTH 1R. In this research proposal we plan to: 1) Characterize the mechanisms of ligand- and cell-specific signaling, regulation, and trafficking of the PTH1R and the PTH2R in VSMC;2) Define the molecular events underlying the anti-mitogenic activity of the PTH1R and PTH2R on VSMC proliferation;3) Define the effects of PTH1R and PTH2R on proliferation of primary VSMC and following in vivo arterial injury.